Monogenic mimics of Behçet's disease in the young.

OBJECTIVES: Monogenic autoinflammatory disorders (AID) and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet's disease (BD). We aimed to retrospectively describe the clinical and laboratory features of 11 paediatric cases referred for suspected BD who turned out to have an alternative, monogenic disease mimicking BD. METHODS: Retrospective, paediatric BD specialist multicentre case series. Next generation sequencing (NGS) or conventional candidate gene screening approaches were utilized, facilitated in some cases by functional assays. RESULTS: Eleven children referred with suspected BD underwent genetic screening because of atypical BD features, and/or presentation before age 5 years. Eight patients (73%) were Caucasian, two were Pakistani and one was Turkish; 55% were female. A positive family history of BD was reported in 54% cases. The median age of disease onset was 0.6 (range 0.2-2.3) years. All had systemic inflammation and oral ulceration; 5/11 had genital ulceration; 3/11 had ocular involvement; and 9/11 had cutaneous manifestations. Nine/11 had known disease-causing genetic mutations in: TNFAIP3 (n = 2), WDR1 (n = 2), NCF1, AP1S3, LYN, MEFV and GLA. The remaining two cases each had novel variants in STAT1 and TNFRSF1A. CONCLUSION: Rare monogenic diseases can mimic BD, particularly when presenting early in life. These observations are now informing a strategy to explore screening for genetic mimics of BD in a UK cohort of children and adults to better understand the proportion of UK BD patients who may in fact have an underlying monogenetic diagnosis.

Aquaporin-4 IgG antibody-related disorders in patients with juvenile systemic lupus erythematosus.

OBJECTIVE: The aim of this study was to: (a) screen a large group of unselected patients with juvenile systemic lupus erythematosus for anti-aquaporin 4 antibodies (AQP4-Ab); (b) identify clinical and laboratory predictors of the presence of AQP4-Ab positivity in juvenile systemic lupus erythematosus. METHODS: Sera from 90 patients with juvenile systemic lupus erythematosus were tested for the presence of AQP4-Ab using a cell-based assay. Demographics, clinical and immunological features, treatment received were summarized. Fisher's exact test was used to identify clinical predictors of positivity for AQP4-Ab. RESULTS: Five of 90 (5.5%) patients tested positive for AQP4-Ab, all of which had neurological involvement, mainly transverse myelitis and optic neuritis. AQP4-Ab-positive patients were more likely to have neurological symptoms (P = 0.002), less likely to experience dermatological manifestations (P = 0.045), and less likely to have detectable anti-dsDNA antibodies (P = 0.022). These patients were also more likely to have received anti-epileptic (P = 0.023) and anti-coagulant (P = 0.007) drugs. CONCLUSIONS: The findings of this study indicate that some patients with juvenile systemic lupus erythematosus develop antibodies against aquaporin-4 and may be at risk of developing a neurological clinical phenotype. We suggest that all juvenile systemic lupus erythematosus patients should be systematically screened for the presence of AQP4-Ab and this may help identify a high risk for neurological involvement in juvenile systemic lupus erythematosus.

Systemic juvenile idiopathic arthritis: The Great Ormond Street Hospital experience (2005-2021).

Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first-line treatment. We conducted a retrospective case notes review of patients diagnosed with sJIA over a 16-year period (October 2005-October 2021) at Great Ormond Street Hospital for Children. We describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course. We examined our data, which spanned a period of changing therapeutic landscape, to try and identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not. A total of 76-children (female n = 40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6-14.1); 36% (27/76) presented with suspected or confirmed macrophage activation syndrome. A biologic disease-modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n = 21/76) of the cohort; however, at last review, 84% (n = 64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n = 67/76) of the cohort at last review; however, only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3 months of diagnosis compared to those who did not (90% vs. 53%, p = 0.002). Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single-centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARDs. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required.

Pulmonary fibrosis presenting as an early manifestation of microscopic polyangiitis.

Microscopic polyangiitis (MPA) is a systemic small vessel vasculitis that is included in the pulmonary-renal syndromes. Although glomerulonephritis represents the major clinical feature of MPA indicative of renal involvement, diffuse alveolar haemorrhage is the classic manifestation of pulmonary involvement. However, pulmonary fibrosis is a less frequently reported pulmonary manifestation. Herein we describe a patient who was diagnosed with MPA presenting with radiographic evidence of pulmonary interstitial fibrosis as an early clinical manifestation accompanied by constitutional symptoms such as fever and weight loss. We also include a short literature review focusing on the association between pulmonary fibrosis and MPA.

Spectrum of Neuroradiologic Findings Associated with Monogenic Interferonopathies.

The genetic interferonopathies are a heterogeneous group of disorders thought to be caused by the dysregulated expression of interferons and are now commonly considered in the differential diagnosis of children presenting with recurrent or persistent inflammatory phenotypes. With emerging therapeutic options, recognition of these disorders is increasingly important, and neuroimaging plays a vital role. In this article, we discuss the wide spectrum of neuroradiologic features associated with monogenic interferonopathies by reviewing the literature and illustrate these with cases from our institutions. These cases include intracerebral calcifications, white matter T2 hyperintensities, deep WM cysts, cerebral atrophy, large cerebral artery disease, bilateral striatal necrosis, and masslike lesions. A better understanding of the breadth of the neuroimaging phenotypes in conjunction with clinical and laboratory findings will enable earlier diagnosis and direct therapeutic strategies.

Endothelial injury and repair in systemic vasculitis of the young.

OBJECTIVE: Endothelial injury is central to the pathogenesis of vasculitis. The purpose of this study was to assess how indices of endothelial injury and repair change during different stages of disease activity in children with primary systemic vasculitis (PSV). METHODS: Fifty children with PSV, 17 children with nonvasculitic inflammatory diseases (pediatric inflammatory disease controls), 35 healthy age- and sex-matched pediatric controls, and 27 healthy adult controls were included in the study. Biomarkers examined were endothelial microparticles (EMPs), circulating endothelial cells (CECs), angiogenic growth factors, and endothelial progenitor cells (EPCs). EMP binding to annexin V, EMPs expressing CD144 or E-selectin, and EPCs expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34 were examined by flow cytometry. CECs were enumerated using immunomagnetic bead extraction techniques, and VEGF and angiopoietin 2 (Ang-2) were measured by enzyme-linked immunosorbent assay. RESULTS: Levels of CD144+ EMPs, CECs, VEGF, and EPCs were all significantly elevated in children with active vasculitis as compared with healthy children, and the levels declined with remission-inducing therapy in the individual patients. Treatment-naive patients with active disease had significantly higher levels of VEGF and Ang-2 than did those with active disease who were receiving treatment, although the levels of CECs and EMPs remained high in both of these groups. CONCLUSION: Elevation of the levels of CECs, EMPS, EPCs, VEGF, and Ang-2 occurs during active vasculitis in children. EPC responses to active vasculitis are different in children as compared with that observed in adults with vasculitis, and both CECs and EMPs can be used to monitor disease activity in children with vasculitis.

Persistent circulating platelet and endothelial derived microparticle signature may explain on-going pro-thrombogenicity after acute coronary syndrome.

AIMS: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. MPs are elevated in the circulation of patients with coronary artery disease (CAD) and have pro-thrombotic potential. However, limited data exists on MP signature over time following an acute coronary event. METHODS & RESULTS: Circulating total annexin v + (Anv+) MPs of endothelial (EMP), platelet (PMP), monocyte (MMP), neutrophil (NMP) and smooth muscle cell (SMMP) origin were quantified by flow cytometry. 13 patients with acute coronary syndrome (ACS) were prospectively enrolled and 12 patients with stable angina (SA) were included as a comparator group. A panel of MP was measured at baseline, after percutaneous coronary intervention (PCI) and at days 1, 7, 30 and 6 months. Intra & inter group comparison was made between various time points. MP mediated thrombin generation was measured by recording lag phase, velocity index, peak thrombin and endogenous thrombin potential at these time points and compared with healthy controls. The total AnV+ MP levels were similar in ACS and SA groups at baseline, peaked immediately after PCI and were at their lowest on day 1. PMP & EMP levels remained significantly elevated in ACS patients at 6 months when compared to SA. No such difference was noted with NMP, MMP and SMMP. Patients with coronary artery disease showed abnormal thrombograms when compared to controls. Peak thrombin (nano moles) was significantly higher in CAD when compared to controls (254 IQR [226, 239] in ACS, 255 IQR [219, 328] in SA and 132 IQR [57, 252] in controls; p = 0.006). Differences in thrombin generation between ACS and SA were not significant (p = 1). Furthermore, thrombin parameters remained abnormal in ACS & SA patients at 6 months. CONCLUSIONS: Total MP and individual MP phenotypes were significantly elevated after PCI reflecting endothelial injury. Elevated PMP and EMP levels at 6 months in ACS patients is suggestive of on-going inflammation, endothelial injury and may explain on-going pro-thrombogenicity seen up to 6 months after ACS despite dual antiplatelet therapy.

MRI Patterns in Pediatric CNS Hemophagocytic Lymphohistiocytosis.

BACKGROUND AND PURPOSE: Neuroimaging has an important role in detecting CNS involvement in children with systemic or CNS isolated hemophagocytic lymphohistiocytosis. We characterized a cohort of pediatric patients with CNS hemophagocytic lymphohistiocytosis focusing on neuroradiologic features and assessed whether distinct MR imaging patterns and genotype correlations can be recognized. MATERIALS AND METHODS: We retrospectively enrolled consecutive pediatric patients diagnosed with hemophagocytic lymphohistiocytosis with CNS involvement treated at 2 pediatric neurology centers between 2010 and 2018. Clinical and MR imaging data were analyzed. RESULTS: Fifty-seven children (40 primary, 70%) with a median age of 36 months (interquartile range, 5.5-80.8 months) were included. One hundred twenty-three MR imaging studies were assessed, and 2 broad imaging patterns were identified. Pattern 1 (significant parenchymal disease, 32/57, 56%) was seen in older children (P = .004) with worse clinical profiles. It had 3 onset subpatterns: multifocal white matter lesions (21/32, 66%), brainstem predominant disease (5, 15%), and cerebellitis (6, 19%). All patients with the brainstem pattern failed to meet the radiologic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. An attenuated imaging phenotype (pattern 2) was seen in 25 patients (44%, 30 studies) and was associated with younger age. CONCLUSIONS: Distinct MR imaging patterns correlating with clinical phenotypes and possible genetic underpinnings were recognized in this cohort of pediatric CNS hemophagocytic lymphohistiocytosis. Disruptive mutations and missense mutations with absent protein expression correlate with a younger onset age. Children with brainstem and cerebellitis patterns and a negative etiologic work-up require directed assessment for CNS hemophagocytic lymphohistiocytosis.

The lived experience of juvenile idiopathic arthritis in young people receiving etanercept.

BACKGROUND: This study explores young people's daily experiences of living with Juvenile Idiopathic Arthritis (JIA) and their thoughts, beliefs and feelings related to the biological drug Etanercept, prescribed as part of their treatment. METHODS: An Interpretive Phenomenological approach was used to allow in-depth examinations of the young people's personal accounts of their lived experiences. Data were obtained from 6 young people between the ages of 10-13 years, from one tertiary institution's Paediatric Rheumatology department using audio-taped open-ended interviews. RESULTS: The transcripts yielded seven thousand words of data and two hundred significant statements, which were reduced to five themes; 1) Who understands me, 2) Medicines and injections, 3) Challenges of schooling and friendships, 4) Being different, and 5) Exclusion from sports. There were marked similarities between the young people's statements; however, there were also some striking differences. The theme 'Who understands me' yielded the biggest section of data, but also produced the biggest disparity between the young people. Two patients were very clear that they thought everyone 'understands', whilst two other patients held the belief that 'no one understood'. This paper explores these statements in further detail. CONCLUSIONS: The findings from this study can give healthcare professionals novel insight into the likely reactions to treatment for JIA and, through this, enable them to offer improved support, education and early intervention before these issues become a concern. This study also provides insight into the emotional resilience of young people with JIA.

Evaluation of magnetic resonance imaging abnormalities in juvenile onset neuropsychiatric systemic lupus erythematosus.

The aim of this study was to describe the abnormalities identified with conventional MRI in children with neuropsychiatric systemic lupus erythematosus (NPSLE). This was single-centre (Great Ormond Street Hospital, London) retrospective case series of patients with juvenile NPSLE seen in 2003-2013. Brain MR images of the first episode of active NPSLE were reviewed. All patients fulfilled the 1999 ACR case definitions for NPSLE syndromes. Presenting neuropsychiatric manifestations, immunological findings and treatment are reported. Results are expressed as median and ranges or percentages. Fisher's exact test was used to identify clinical predictors of abnormal MRI. A total of 27 patients (22 females), median age 11 years (4-15), were identified. Presenting clinical symptoms included the following: headaches (85.1 %), mood disorder/depression (62.9 %), seizures (22.2 %), acute psychosis (18.5 %), cognitive dysfunction (14.8 %), movement disorder (14.8 %), acute confusional state (14.8 %), aseptic meningitis (7.4 %), demyelinating syndrome (3.7 %), myelopathy (3.7 %), dysautonomia (3.7 %) and cranial neuropathy (3.7 %). The principal MR findings were as follows: (1) absence of MRI abnormalities despite signs and symptoms of active NPSLE (59 %); (2) basilar artery territory infarction (3 %); (3) focal white matter hyperintensities on T2-weighted imaging (33 %); (4) cortical grey matter lesions (3 %); and (5) brain atrophy (18.5 %). The presence of an anxiety disorder strongly associated with abnormal MRI findings (p = 0.008). In over half the children with NPSLE, no conventional MRI abnormalities were observed; white matter hyperintensities were the most commonly described abnormalities. Improved MR techniques coupled with other alternative diagnostic imaging modalities may improve the detection rate of brain involvement in juvenile NPSLE.

A low balance between microparticles expressing tissue factor pathway inhibitor and tissue factor is associated with thrombosis in Behçet's Syndrome.

Thrombosis is common in Behçet's Syndrome (BS), and there is a need for better biomarkers for risk assessment. As microparticles expressing Tissue Factor (TF) can contribute to thrombosis in preclinical models, we investigated whether plasma microparticles expressing Tissue Factor (TF) are increased in BS. We compared blood plasma from 72 healthy controls with that from 88 BS patients (21 with a history of thrombosis (Th+) and 67 without (Th-). Using flow cytometry, we found that the total plasma MP numbers were increased in BS compared to HC, as were MPs expressing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p < 0.0001). Amongst BS patients, the Th+ group had increased total and TF positive MP numbers (both p ≤ 0.0002) compared to the Th- group, but had a lower proportion of TFPI positive MPs (p < 0.05). Consequently, the ratio of TFPI positive to TF positive MP counts (TFPI/TF) was significantly lower in Th+ versus Th- BS patients (p = 0.0002), and no patient with a TFPI/TF MP ratio >0.7 had a history of clinical thrombosis. We conclude that TF-expressing MP are increased in BS and that an imbalance between microparticulate TF and TFPI may predispose to thrombosis.

Cardiovascular status after Kawasaki disease in the UK.

OBJECTIVE: Kawasaki disease (KD) is an acute vasculitis that causes coronary artery aneurysms (CAA) in young children. Previous studies have emphasised poor long-term outcomes for those with severe CAA. Little is known about the fate of those without CAA or patients with regressed CAA. We aimed to study long-term cardiovascular status after KD by examining the relationship between coronary artery (CA) status, endothelial injury, systemic inflammatory markers, cardiovascular risk factors (CRF), pulse-wave velocity (PWV) and carotid intima media thickness (cIMT) after KD. METHODS: Circulating endothelial cells (CECs), endothelial microparticles (EMPs), soluble cell-adhesion molecules cytokines, CRF, PWV and cIMT were compared between patients with KD and healthy controls (HC). CA status of the patients with KD was classified as CAA present (CAA+) or absent (CAA-) according to their worst-ever CA status. Data are median (range). RESULTS: Ninety-two KD subjects were studied, aged 11.9 years (4.3-32.2), 8.3 years (1.0-30.7) from KD diagnosis. 54 (59%) were CAA-, and 38 (41%) were CAA+. There were 51 demographically similar HC. Patients with KD had higher CECs than HC (p=0.00003), most evident in the CAA+ group (p=0.00009), but also higher in the CAA- group than HC (p=0.0010). Patients with persistent CAA had the highest CECs, but even those with regressed CAA had higher CECs than HC (p=0.011). CD105 EMPs were also higher in the KD group versus HC (p=0.04), particularly in the CAA+ group (p=0.02), with similar findings for soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1. There was no difference in PWV, cIMT, CRF or in markers of systemic inflammation in the patients with KD (CAA+ or CAA-) compared with HC. CONCLUSIONS: Markers of endothelial injury persist for years after KD, including in a subset of patients without CAA.

Chronic respiratory failure in a patient with type I Arnold-Chiari malformation (ACM1) and syringomyelia.

We present the case of a young adult with type I Arnold-Chiari malformation (AMC1) and syringomyelia who developed central sleep apnoea and chronic respiratory failure, successfully treated with nocturnal noninvasive positive pressure ventilation ventilation (NIPPV). An extensive syringomyelic cavity (from bulbar to L4 segment) with severe impairment of the IX cranial nerve was documented and remains, although reduced, after the neurosurgical treatment. At baseline evaluation, the patient showed a moderate restrictive ventilatory defect, severe hypercapnic respiratory failure, abnormal control of breathing characterized by the absence of response to hypoxia and hypercapnia, and severe nocturnal central apnoeas. Nocturnal NIPPV was then started in the A/C mode with an improvement in blood gas values. Further evaluations were performed 10 and 18 months later. A progressive significant improvement of lung volumes, both in sitting and supine position, associated with a slight improvement of blood-gas values were observed. Nonetheless, the breathing pattern abnormalities persisted. Polysomnographic evaluation during mechanical ventilation showed a normalization of breathing pattern with arterial oxygen saturation (SaO2) > 90% throughout the night.

Management of Kawasaki disease.

Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A-BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) ß pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFα, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances.

Quantitative detection of circulating endothelial cells in vasculitis: comparison of flow cytometry and immunomagnetic bead extraction.

BACKGROUND: Circulating endothelial cells (CECs) are biomarkers for endothelial cell (EC) injury and are quantified using immunomagnetic bead extraction (IBE), or flow cytometry (FC). Reports suggest that there is good agreement between these methods for CEC quantification. OBJECTIVES: We examined levels of agreement between these techniques in children with systemic vasculitis. METHODS: We added HUVEC or human pulmonary artery EC to whole blood to optimize FC gating strategies for EC. EC-optimized FC was then compared with IBE for CEC enumeration in 25 children with vasculitis and 20 healthy controls. RESULTS: Using Bland-Altman analysis, agreement between IBE and EC-optimized FC was poor in children with vasculitis (n = 25) and healthy controls (n = 20): IBE consistently detected higher values than the EC-optimized FC method: the mean difference between the two techniques was 60 CECs mL(-1), 95% CI +/-374 CECs mL(-1) (paired analyses of 45 individuals). Agreement was poorest for vasculitis patients: mean difference (IBE - EC-optimized FC) 120 CECs mL(-1), 95% CI +/-460 CECs mL(-1) (P = 0.018). We identified three reasons for this discrepancy: (i) sub-optimal FC gating parameters previously used for detecting CECs; (ii) inherent lack of sensitivity of FC compared with IBE for CEC rare event detection; and (iii) use of lysis buffers required for FC causing CEC lysis. CONCLUSIONS: There was poor agreement between EC-optimized FC and IBE for the quantification of CECs from children with active vasculitis and controls. We emphasize that in this clinical setting the two techniques are not directly comparable when comparing results obtained using these different methodologies.